1. Academic Validation
  2. Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility

Influenza A and B viruses with reduced baloxavir susceptibility display attenuated in vitro fitness but retain ferret transmissibility

  • Proc Natl Acad Sci U S A. 2020 Apr 14;117(15):8593-8601. doi: 10.1073/pnas.1916825117.
Jeremy C Jones 1 Philippe Noriel Q Pascua 2 Thomas P Fabrizio 2 Bindumadhav M Marathe 2 Patrick Seiler 2 Subrata Barman 2 Richard J Webby 2 Robert G Webster 1 Elena A Govorkova 2
Affiliations

Affiliations

  • 1 Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678 [email protected] [email protected].
  • 2 Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN 38105-3678.
Abstract

Baloxavir marboxil (BXM) was approved in 2018 for treating influenza A and B virus infections. It is a first-in-class inhibitor targeting the endonuclease activity of the virus polymerase acidic (PA) protein. Clinical trial data revealed that PA amino acid substitutions at residue 38 (I38T/F/M) reduced BXM potency and caused virus rebound in treated patients, although the fitness characteristics of the mutant viruses were not fully defined. To determine the fitness impact of the I38T/F/M substitutions, we generated recombinant A/California/04/2009 (H1N1)pdm09, A/Texas/71/2017 (H3N2), and B/Brisbane/60/2008 viruses with I38T/F/M and examined drug susceptibility in vitro, enzymatic properties, replication efficiency, and transmissibility in ferrets. Influenza viruses with I38T/F/M substitutions exhibited reduced baloxavir susceptibility, with 38T causing the greatest reduction. The I38T/F/M substitutions impaired PA endonuclease activity as compared to that of wild-type (I38-WT) PA. However, only 38T/F A(H3N2) substitutions had a negative effect on polymerase complex activity. The 38T/F substitutions decreased replication in cells among all viruses, whereas 38M had minimal impact. Despite variable fitness consequences in vitro, all 38T/M viruses disseminated to naive ferrets by contact and airborne transmission, while 38F-containing A(H3N2) and B viruses failed to transmit via the airborne route. Reversion of 38T/F/M to I38-WT was rare among influenza A viruses in this study, suggesting stable retention of 38T/F/M genotypes during these transmission events. BXM reduced susceptibility-associated mutations had variable effects on in vitro fitness of influenza A and B viruses, but the ability of these viruses to transmit in vivo indicates a risk of their spreading from BXM-treated individuals.

Keywords

I38T substitution; PA protein; baloxavir marboxil; endonuclease inhibitor; influenza.

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